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Molecular and Cellular Biology, March 2007, p. 1696-1705, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01760-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Neuropilin-1 Is a Direct Target of the Transcription Factor E2F1 during Cerebral Ischemia-Induced Neuronal Death In Vivo{triangledown}

Susan X. Jiang,1,§ Melissa Sheldrick,1,2,§ Angele Desbois,1 Jacqueline Slinn,1 and Sheng T. Hou1,2*

NRC Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road Building M-54, Ottawa, Ontario K1A 0R6, Canada,1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada2

Received 18 September 2006/ Returned for modification 30 October 2006/ Accepted 6 December 2006

The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1+/+ and E2F1–/– mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1–/– neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1–/– neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.

* Corresponding author. Mailing address: NRC Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Bldg. M-54, Ottawa, ON, Canada K1A 0R6. Phone: (613) 993-7764. Fax: (613) 941-4475. E-mail: sheng.hou{at}nrc-cnrc.gc.ca.

{triangledown} Published ahead of print on 18 December 2006.

§ S.X.J. and M.S. contributed equally to this study.

Molecular and Cellular Biology, March 2007, p. 1696-1705, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01760-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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